Copper Deficiency Caused by Excessive Alcohol Consumption Shunichi Shibazaki,1 Shuhei Uchiyama,2 Katsuji Tsuda,3 Norihide Taniuchi4

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Findings that shed new light on the possible pathogenesis of a disease or an adverse effect BMJ Case Reports: first published as 10.1136/bcr-2017-220921 on 26 September 2017. Downloaded from Case report Copper deficiency caused by excessive alcohol consumption Shunichi Shibazaki,1 Shuhei Uchiyama,2 Katsuji Tsuda,3 Norihide Taniuchi4

1Department of Emergency Summary managed by crawling. A day before his visit to our and General Internal Medicine, Copper deficiency is a disease that causes cytopaenia hospital, his behaviour became unintelligible, and Hitachinaka General Hospital, and neuropathy and can be treated by copper he was brought to our hospital by ambulance. He Hitachinaka, Ibaraki, Japan supplementation. Long-term tube feeding, long-term had a history of hypertension and dyslipidaemia 2Department of General Internal total parenteral nutrition, intestinal resection and and took amlodipine and rosuvastatin. He has no Medicine, Tokyo Bay Urayasu history of surgery and he did not take zinc medica- Ichikawa Medical Center, ingestion of zinc are known copper deficiency risk Urayasu, Chiba, Japan factors; however, alcohol abuse is not. In this case, a tion or supplementation. 3Department of Nephrology, 71-year-old man had difficulty waking. He had a history Vital signs were the following: blood pressure Suwa Central Hospital, Chino, of drinking more than five glasses of spirits daily. He was 96/72 mm Hg, pulse 89/min, body temperature Nagano, Japan well until 3 months ago. A month before his visit to our 36.7°C, respiration rate 15/min at time of visit. 4Department of hospital, he could not eat meals but continued drinking. He lost consciousness and could not understand Gastroenterology and Internal He had macrocytic anaemia on admission. Copper where he was or respond to instructions. His ocular Medicine, Suwa Central and ceruloplasmin levels were markedly low, and we conjunctiva was yellow tinged and he had a flap- Hospital, Chino, Nagano, Japan diagnosed copper deficiency. There were no other known ping tremor. He had an abdominal bulge and no risk factors for copper deficiency. After he began drinking knock pain around his liver. He had brown diar- Correspondence to rhoea, not tarry stool. He was unable to stand up Dr Shunichi Shibazaki, cocoa as a copper supplement, the anaemia ameliorated sn1. shibazaki@gmail. com and he was able to walk. This is the first report showing to both knees. Babinski reflection was positive. He alcohol abuse as a risk factor for copper deficiency. was uncooperative with our physical examination, Accepted 12 September 2017 and as such, a detailed neurological examination including serial exams was not possible. copyright. Background Investigations Copper deficiency is a disease that causes blood cell Blood tests revealed a white blood cell count of abnormalities such as anaemia and leucopaenia1, 5190/μL without abnormal fractionation. His and neurological symptoms such as neuropathy, haemoglobin (Hb) was 7.8 g/dL (normal range myelopathy and vision loss.2 It needs to be differ- 13.5–17.6 g/dL), mean corpuscular volume was entiated from vitamin B 12 deficiency. Although the

107.4 fl (normal range 83–93 fl), reflecting macro- http://casereports.bmj.com/ precise frequency is unknown, primary copper defi- 4 cytic anaemia. Platelet count was 11.7×10 /μL ciency is relatively rare because copper is univer- 4 4 3 (normal range 13.1×10 -36.2×10 /μL), reflecting sally included in the diet. Therefore, it should be mild thrombocytopaenia. Aspartate aminotrans- suspected when the patient has a known risk factor. ferase was 477 IU/L (normal range 7-97 IU/L), Current known risk factors include special nutri- alanine aminotransferase was 155 IU/L (normal tional conditions such as long-term tube feeding4 5 range 6–43 IU/L), blood urea nitrogen was 26.7 and long-term total parenteral nutrition , gastro- mg/dL (normal range 10–20 mg/dL), creatinine intestinal problems such as postgastrectomy6 and 7 2.41 mg/dL (normal range 0.6–1.0 mg/dL), that is, postobesity surgery and other conditions, such as liver and kidney dysfunction were also observed. ingestion of zinc.8 There are also several copper 9 Blood glucose level was normal (137 mg/dL). on 26 September 2021 by guest. Protected deficiency case reports of unknown causes, , which Ammonia level increased up to 166 μg/dL (normal suggests that there are other risk factors. Currently range 30–80 μg/dL). His serum ferritin also signifi- in the literature, there are no case reports of alcohol cantly increased up to 9506 ng/mL (normal range abuse as a risk for copper deficiency. We experi- 39.4–340 ng/mL). C-reactive protein was 5.89 enced a case of copper deficiency due to alcohol mg/dL (normal range 0.0–0.3 mg/dL). However, abuse without other known risk factors. urinary white blood cells and bacterial urine were negative, thus excluding pyelonephritis. In addi- Case presentation tion, ascites had no bacteria, while white blood A 71-year-old man was a long-term alcoholic that cell count in ascites was 32/μL, thus also excluding drank more than five glasses of spirits daily. Begin- spontaneous bacterial peritonitis. The following T o cite: Shibazaki S, ning 3 months ago, he began to eat less at meals data are reference values because these blood tests Uchiyama S, Tsuda K, et al. that consisted mostly of raw fish and meat and were investigated after vitamin ingestion at the BMJ Case Rep Published Online First: [please continued to drink alcohol. However, he had no emergency department; serum vitamin B1 91 ng/ include Day Month Year]. other problems in daily life. One month ago, he mL (normal range 24-66 ng/mL) and serum vitamin doi:10.1136/bcr-2017- could no longer eat meals but continued drinking. B12 >1500 pg/mL (normal range 180-914 pg/mL). 220921 At about this time, he became unable to walk and Prothrombin time (PT) was 16.5 s (normal range

Shibazaki S, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220921 1 Findings that shed new light on the possible pathogenesis of a disease or an adverse effect BMJ Case Reports: first published as 10.1136/bcr-2017-220921 on 26 September 2017. Downloaded from

Outcome and follow-up Serum copper and ceruloplasmin recovered rapidly, serum ferritin declined and blood cell count recovered after just a few days of drinking cocoa. His delirium also disappeared rapidly from the day after starting cocoa. Moreover, activity of daily life recovered rapidly (figure 1). Because he became cooperative with medical treatment, we used diuretics and BCAA sequen- tially. Eventually, he could walk on his own and was discharged on the 74th day and was ambulatory. The blood cells subsequently recovered: Hb 14.3 g/dL, however, Babinski reflexion remained positive 4 months after the start of copper supplementation. He continued abstinence after being discharged from our hospital and has had no relapse after 2 years of follow-up.

Discussion This is the first case report clinically, suggesting that excessive alcohol consumption can be a risk factor for copper deficiency. Copper is an essential element in the body, absorbed from the jejunum to duodenum,10 and it spreads throughout the body via the liver. It acts as a coenzyme for many enzymes, and in particular, plays an important role in the bone marrow and nerve system.11 Therefore, copper deficiency can result in blood cell abnormalities such as various types of anaemia (microcytic, normocytic, macrocytic anemia) and leucopenia1, and neurologic Figure 1 Clinical course of this case. Initially, symptoms did not symptoms such as neuropathy, myelopathy, and vision loss2. In improve with multiple treatments. However, it improved dramatically particular, it is important to differentiate this from vitamin B12 with copper supplementation via cocoa. ADL, activity of daily life; BCAA, deficiency because the phenotypes are similar. Copper supple- branched chain amino acid; Hb, haemoglobin; Ret, reticulocyte. mentation recovers blood cell abnormalities favourably.3 For

neurological symptoms, however, the recovery is partial, and it copyright. is thought that neurological symptoms will become irreversible 11–14 s), PT% was 51.9% (normal range 80–120%). Head CT 12 revealed no abnormality, however, abdominal CT showed an if treatment is delayed. . Therefore, it is important to diagnose advanced fatty liver and a massive amount of ascites. copper deficiency and start treatment early. Since he ramped and was uncooperative with our investiga- Copper deficiency may be overlooked. Although the exact tion, it was impossible to conduct a detail examination such as frequency of copper deficiency is unknown, primary copper deficiency is considered relatively rare as copper is included in with upper gastrointestinal endoscope to rule out gastrointes- 3 13 tinal bleeding. MRI of the spine and brain to confirm the cause most diets. Typically, clinician awareness is low, which makes http://casereports.bmj.com/ of being unable to walk was also not possible. correct diagnosis difficult. Generally, we suspect copper deficiency if the patient has a known risk factor. Known risk factors Treatment include special nutritional conditions such as long-term tube feeding4 and long-term parenteral nutrition5 or gastrointestinal Initially, we suspected vitamin B12 deficiency with hepatic 6 7 encephalopathy and prerenal renal failure. Therefore, intrave- problems such as postgastrectomy and postobesity surgery or other conditions, such as zinc intake.8 There are several nous vitamin B12 supplementation (more than 1000 µg daily), 9 branched chain amino acid (BCAA) administration and replace- case reports about copper deficiency of unknown cause. This ment fluid were administered. Lactulose was not used because suggests that clinically there may be other risk factors. he was not constipated but rather had diarrhoea. Lorazepam was This case clinically suggests that excessive alcohol consumption can be a risk factor for copper deficiency. There are three also administered to prevent alcohol withdrawal. Antibiotics on 26 September 2021 by guest. Protected were not used because there was no finding to affirm bacterial reasons supporting this. First, the patient did not have any other infection. In addition, corticosteroid was not used because there known risk factors, and he was not a candidate for any other were few findings to suggest acute alcoholic hepatitis such as remarkable cause other than excessive alcohol consumption. fever, tachycardia and liver knock pain. Moreover, he had no recurrence after abstinence and after the These treatments, however, did not recover symptoms, which copper supplementation. It was possible that a decreased volume instead worsened. For that reason, we suspected another disease: of meals might have affected the onset of copper deficiency, copper deficiency mimicking vitamin B12 deficiency. Later on, however, this alone could not explain the progression speed of tests showed that the serum copper level was under 2 μg/dL the disease such that the condition emerged after only 3 months (normal range 68–128 μg/dL), and the serum ceruloplasmin of not eating properly. It is most likely that prior to 3 months level was 8 mg/dL (normal range 21-37 mg/dL). Therefore, we ago he had small meals. Moreover, he was eating fish and meat, diagnosed that the main disease was not vitamin B12 deficiency which contain ample amounts of copper. Therefore, we think but copper deficiency instead. Additionally, his delirium wors- that it was less likely that he became copper deficient from ened with strong outbursts, thus treatment continuation was diet alone. In previous reports, it takes more than a half year extremely difficult. His family asked that we stop aggressive to 1 year for copper deficiency to emerge in long-term tube 4 5 medication treatment and try only two to three cups of cocoa, feeding or parenteral nutrition. Thus, an insufficient intake which can supplement copper daily. by itself would not explain the short 3-month course. Second,

2 Shibazaki S, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220921 Findings that shed new light on the possible pathogenesis of a disease or an adverse effect BMJ Case Reports: first published as 10.1136/bcr-2017-220921 on 26 September 2017. Downloaded from experimental data from rat studies14 by Fields et al reported We experienced a case of copper deficiency due to an exces- that copper deficiency with organ disorder did not occur in rats sive habitual alcohol consumption. We encourage clinicians to fed a copper deficient diet. However, organ disorders such as suspect copper deficiency when patients with an alcohol habit anaemia occurred in rats fed a copper deficient diet and 20% have blood cell abnormalities and neurological symptoms. ethanol for 6 weeks. Although this was experimental rat data, Further investigation is needed to elucidate the mechanism it suggests that alcohol consumption causes copper deficiency. causing copper deficiency with excessive alcohol consumption. 15 Third, there is human epidemiological data. Zhang et al Contributors Authors’ contributions are following: SS, corresponding author wrote reported that serum copper levels in healthy Chinese volunteers the draft. SU, KT and NT revised the article for intellectual content. who drank regularly were significantly lower than that who did Competing interests None declared. not have a drinking habit. Although it is unknown whether the Patient consent Obtained. organ disorder of copper deficiency occurred in this report, it Provenance and peer review Not commissioned; externally peer reviewed. suggests that drinking alcohol affects human copper metabolism. Based on these supporting studies, this case clinically suggests Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which that alcohol abuse can be a cause of copper deficiency. Unfor- permits others to distribute, remix, adapt, build upon this work non-commercially, tunately, the exact mechanism whereby alcohol causes copper and license their derivative works on different terms, provided the original work deficiency is unknown. From the point of view of rapid disease is properly cited and the use is non-commercial. See: http://creativecommons.org/ progression, new mechanisms may be considered, such as copper licenses/by- nc/4. 0/ consumption or excretion promotion rather than a problem with © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) intestinal absorption. 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. An effective method of copper supplementation is oral administration of cocoa. Although the amount of necessary copper supplementation is not established, it is said to be 2 to 6 mg/ References 12 16 1 Gregg XT, Reddy V, Prchal JT. Copper deficiency masquerading as myelodysplastic day, which is several times the required amount of copper, syndrome. Blood 2002;100:1493–5. 17 which as an essential dietary micronutrient is 0.9 mg/day . 2 Kumar N, Gross JB, Ahlskog JE. Copper deficiency myelopathy produces a clinical However, when copper is deficient, absorption efficiency from picture like subacute combined degeneration. Neurology 2004;63:33–9. the intestinal tract increases18 if there are no problems with the 3 Gabreyes AA, Abbasi HN, Forbes KP, et al. Hypocupremia associated cytopenia and myelopathy: a national retrospective review. Eur J Haematol 2013;90:1–9. intestinal tract, and thus an extreme increase may not be neces- 4 Chen CC, Takeshima F, Miyazaki T, et al. Clinicopathological analysis of hematological sary. In this case, we chose cocoa as a copper supplement. Cocoa disorders in tube-fed patients with copper deficiency. Intern Med 2007;46:839–44. contains a moderate amount of copper and is a convenient 5 Fuhrman MP, Herrmann V, Masidonski P, et al. Pancytopenia after removal of copper 19 20 from total parenteral nutrition. JPEN J Parenter Enteral Nutr 2000;24:361–6. beverage. This cocoa contained about 0.2 mg of copper per copyright. 6 Imataki O, Ohnishi H, Kitanaka A, et al. Pancytopenia complicated with peripheral cup, and as such, he consumed 0.4 to 0.6 mg/day. His symp- neuropathy due to copper deficiency: clinical diagnostic review. Intern Med toms dramatically improved even with this small amount of 2008;47:2063–5. supplementation. 7 Kumar P, Hamza N, Madhok B, et al. Copper deficiency after gastric bypass for morbid This case report has some limitations. First, it is difficult obesity: a systematic review. Obes Surg 2016;26:1335–42. to precisely distinguish neurological symptoms including 8 sochet AA, Jones A, Riggs CD, et al. A 3-year-old boy with severe anemia and neutropenia. Pediatr Ann 2013;42:15–17. delirium from hepatic encephalopathy and alcohol with- 9 Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc drawal. However, treatment of hepatic encephalopathy or 2006;81:1371–84. alcohol withdrawal did not improve his symptoms, which 10 Collins JF, Prohaska JR, Knutson MD. Metabolic crossroads of iron and copper. Nutr http://casereports.bmj.com/ instead worsened. Meanwhile, his neurological symptoms Rev 2010;68:133–47. 11 stern BR, Solioz M, Krewski D, et al. Copper and human health: biochemistry, such as delirium recovered from the very next day after genetics, and strategies for modeling dose-response relationships. J Toxicol Environ copper supplementation. From this characteristic course, we Health B Crit Rev 2007;10:157–222. presumed that the main pathological condition was copper 12 Jaiser SR, Winston GP, myelopathy Cdeficiency. J Neurol 2010;257:869–81. deficiency. Second, we did not prove that there was a blood 13 Halfdanarson TR, Kumar N, Li CY, et al. Hematological manifestations of copper deficiency: a retrospective review. Eur J Haematol 2008;80:523–31. cell abnormality due to copper deficiency by bone marrow 14 Fields M, Lewis CG. Alcohol consumption aggravates copper deficiency. Metabolism examination. Therefore, it is difficult to distinguish from 1990;39:610–3. blood cell abnormalities due to alcohol toxicity. However, 15 Zhang HQ, Li N, Zhang Z, et al. Serum zinc, copper, and zinc/copper in healthy the dramatic progressive increase in reticulocytes in just a residents of Jinan. Biol Trace Elem Res 2009;131:25–32.

16 prodan CI, Bottomley SS, Holland NR, et al. Relapsing hypocupraemic myelopathy on 26 September 2021 by guest. Protected few days after copper supplementation by cocoa suggests that requiring high-dose oral copper replacement. J Neurol Neurosurg Psychiatry copper deficiency was the main cause. 2006;77:1092–3. 17 Trumbo P, Yates AA, Schlicker S, et al. Dietary Reference Intakes. J Am Diet Assoc 2001;101:294–301. 18 Turnlund JR, Keyes WR, Peiffer GL, et al. Copper absorption, excretion, and retention Learning points by young men consuming low dietary copper determined by using the stable isotope 65Cu. Am J Clin Nutr 1998;67:1219–25. 19 Nagano T, Toyoda T, Tanabe H, et al. Clinical features of hematological disorders ►► Copper deficiency should be part of the differential if patients caused by copper deficiency during long-term enteral nutrition. Intern Med have blood cell abnormalities and neurological symptoms. 2005;44:554–9. ►► Alcohol abuse can be a risk factor for copper deficiency. 20 Nishiwaki S, Iwashita M, Goto N, et al. Predominant copper deficiency during ►► Cocoa can easily replenish copper requirements. prolonged enteral nutrition through a jejunostomy tube compared to that through a gastrostomy tube. Clin Nutr 2011;30:585–9.

Shibazaki S, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220921 3 Findings that shed new light on the possible pathogenesis of a disease or an adverse effect BMJ Case Reports: first published as 10.1136/bcr-2017-220921 on 26 September 2017. Downloaded from

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4 Shibazaki S, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2017-220921